1, 4-bis(d-glucosyl)piperazine and process of preparation



United States Patent 1,4-BIS(D-GLUCOSYL)PIPERAZI1\IE AND PROCESS onPREPARATION Tellis A. Martin, Evansville, Ind., assignor to Mead,Johnson (it Company, Evansville, Ind., a corporation of Indiana NoDrawing. Application October 18, .1956 Serial No. 616,583

2 Claims. c1. 260-4115) This invention relates to a reaction product ofglucose and piperazine and more specifically to 1,4-bis-(D-glucosyl)piperazine having the following structural formula:

of the piperazine compounds described above are noted in the BritishMedical Journal, page 1272, Dec. 5, 1953, and a number of similarpublications which have appeared more recently.

Accordingly the compound of the present invention is useful as ananthelmintic and more particularly as an oxyuricidal agent which hasgreatly reduced toxic side effects and is in general considerably lesstoxic than the prior art piperazine compounds which have been used forthis purpose.

Generally this compound may be administered orally in the form ofwafers, capsules, tablets, powders, liquid suspensions, and the like.The dosage for an adult will usually be from about 2500 to 5000milligrams per day, administered from once to several times daily toachieve the desired therapeutic effect.

The following table will illustrate the relative toxicity of thecompound of the present invention, as compared 1 to the prior artpiperazine hexahydrate and piperazine salts.

TABLE I Toxicity 0;! piperazine-containing compounds Composition: LD(orally) (mgs./kg.) Piperazine hexahydrate 2880 Piperazine adipate(tech) 3035 Piperazine citrate 3400 Mechanical mixture of one mole ofpiperazine and two moles of glucose 2646 1,4-bis(D-glucosyl)piperazine6510 a All values are based upon the piperazine content, and the LDsovalues were determined in white mice, p.o.

J. Pharm. and Pharmacology VI. 711 (October 1954).

c J. Am. Med. Assoc. 161, 515 (1956).

As may be seen from this table, the LD values are stated in terms of thepiperazine content and it should be further noted that there is alsoincluded in that table an LD value for a mechanical mixture of one moleof 2,910,465 Patented Oct. 27, 1959 ICC piperazine and two moles ofglucose which was included to show that the lack of toxic properties ofthe compound of the present invention is an inherent characteristic ofthe compound itself and not a result of dilution of the piperazinecontent by the substitution of large substituents on the parentpiperazine structure. With reference to the prior art piperazine,hexahydrate and piperazine adipate which are used as oxyuricidalagents, the LD values obtained are about 3000 milligrams per kilogramwhich is less than one-half of the LD value for1,4-bis-(D-glucosyl)piperazine which has an LD of 6510 milligrams per kilogram.

The 1,4-bis(D-glucosyl)piperazine of this invention may be readilysynthesized by the direct reaction of glucose and piperazine orpiperazine hexahydrate. Usually the best and quickest results areobtained when glucose and piperazine are heated together at 60 to C. for4 to 10 hours. Increase in temperature and concentrations of thereactants will generally result ina more rapid reaction rate and thereaction is preferably carried out in the presence of an aqueous ornonaqueous solvent.

The product of the present invention is a soft powder having a meltingpoint range of between about 168 and 191 C. with decomposition. Thiswide range in melting point is believed to be due to existence of amixture of different proportions of alpha and beta glucosyl groups inthe final product which may depend upon the partic ular method ofpreparation. The product of the present invention shows an infraredabsorption band at 843 cm.- which is in the range 835 to 855 cm.-characteristic of a D-glucosylamines. The product of the'presen'tinvention is also characterized in that it has rather low solubility inthe usual organic solvents, water and dilute alkaline medium. Theproduct is more readily soluble in strong mineral acids such ashydrochloric acid.

The following are examples of methods for preparing the product of thisinvention:

EXAMPLE 1 p A mixture of 29.3 g. (0.163 mole') of D-glucose'(anhydrous), 14 g. (0.163 mole) of anhydrous piperazine and 850.milliliters of absolute methanol was heated under reflux for fourhours. On cooling, the slightly yellow solid Was collected on a filter,washed with methanol and dried. Yield: 20 g. of M.Pl 190 C. (d). Twoadditional fractions of solid product were obtained by concentrating theabove filtrate: 4 g. of M.P. 184-192" C. (d) and 2 g. of MP. l89-191 C.(d). Total yield: 26 g. (78%, based on glucose). Fraction (1) wasslurried with methanol to give product with M.P. 187-489 C. (d) withdarkening at about C. However, with fast heating this darkening does notoccur until somewhat higher temperatures and as a result higherdecomposition points are obtained.

Analysis.-Calc. for C H N O C, 46.82; H, 7.37; N, 6.83. Found: N, 6.50,6.50.

Less expensive starting materials such as piperazine hexahydrate andglucose monohydrate may be employed in this reaction. Also small amountsof catalyst, such as hydrochloric acid or ammonium chloride, may beemployed. Other alcohols (ethanol, isopropanol, propylene glycol, etc.)may be used as reaction solvent.

EXAMPLE 2 A mechanically stirred mixture of 216 g. (1.2 moles) ofD-glucose, 116.4 g. (0.6 mole) of piperazine hexahydrate and 360 ml. ofpropylene glycol was warmed to about 75 C. by external heating with anoil bath. Complete solution resulted at this p.oint and a filtrationstep may be included here to remove any trace of solid impurity. Then oncontinued heating at 75-80 C. for 10-20 minutes, a cloudiness appearedand the solid product began to precipitate. Then by the use of a Dean-Starke water separator, the theoretical quantity of water was collectedas a benzene-water azeotrope. The reaction temperature of 80-84 C. wasmaintained overthe entire heating period of nine hours by introducingadd1- tional quantities of benzene as necessary (with oil bathtemperature of l-ll0 C.). On allowing the reaction mixture to cool toabout 60 C., 400 ml. of methanol was added and the pale yellow productwas collected on a filter, washed with methanol and dried under reducedpressure by employing rubber sheet over the funnel. Yield: 224 g. (91%of theory); M.P. 176-178 C. (d). Analysis.-Found: C, 47.69; H, 7.37; N,6.83, 6.86. Depending on the concentration of the benzene in thereaction mixture, the reaction temperature and thus the time for thecompletion of the reaction may vary. However, when the reaction wasshortened to four hours,

somewhat inferior yield (70-80%) and quality of product was obtained.Prolonged heating at higher temperatures resulted in decomposition withdarkening of the reaction mixture and a lower yield and an inferiorproduct. In some instances it was noted that an inert atmosphere asnitrogen for the reaction mixture could be used advantageously.

Other glycol solvents, for example ethylene glycol or a mixture ofpropylene glycol and ethylene glycol, may be used as reaction solvent.In some cases, it may be desirous to omit the use of the benzene-waterazeotrope for the removal of water, and instead, employ reducedpressure.

EXAMPLE 3 A mixture of 19.4 g. (0.1 mole) of piperazine hexahydrate, 36g. (0.2 mole) of glucose and 75 ml. of water was warmed on a steam bathuntil solution resulted. Then the mixture was allowed to stand at roomtemperature for two weeks. The resulting colorless product was collectedon a filter and washed with 200 ml. of warm methanol. Yield: 16 g.(39%); M.P. 186-188 C. (d).

Analysis.-Found: N, 7.05, 7.13.

On cooling the above filtrate at 0 C. for about one week, 3 g. of thelower melting form was obtained, M.P. 172-174 C. (d). Total yield: 19 g.(46%).

When a solution of 1.94 g. (0.01 mole) of piperazine hexahydrate, 3.60.g. (0.02 mole) of glucose and enough water to give a total volume of 19ml. was allowed to stand for eighteen days, no solid was obtained.However, on diluting this solution with 80 ml. of methanol a precipitatebegan to form at once. After standing for one hour and filtering, aneighteen percent yield was obtained; M.P. 174-175 C. (d).

However, an increased yield was obtained when a large excess of glucosewas employed: 10.8 g. (0.06 mole) of glucose was dissolved in 12 m1. ofwater by warming. Then 1.94 g. (0.01 mole) of piperazine hexahydrate wasadded and the solution was allowed to stand at room temperature. Afterthree days a solid had separated. After twelve days the mixture wasdiluted with 5 ml. of methanol, and filtered. The residue was washedwith methanol and dried. Yield: 3.3 g. based on the piperazine) ofcolorless solid, M.P. 184-186 C. (d).

EXAMPLE 4:

On stirring together a mixture of 1.94 g. (0.01 mole) of piperazinehexahydrate and 3.60 g. (0.02 mole) of glucose, a syrup was obtained.This was placed in a closed bottle for three weeks. The resultingsemi-solid was triturated with methanol. The precipitate was collectedon a funnel, washed with methanol and dried. Yield: 2.7 g. (66%) of paleyellow solid of M.P. 169- 172 C. (d). Higher yields (80-90%) wereobtained when larger quantities of glucose were employed in thisreaction.

Although this product of the present invention undergoes slow change(partial hydrolysis and mutarotation) in water and dilute alkali, it isunafiected on exposure to the atmosphere or in suspension with anhydrousvehicles such as Carbowax 400 (polyethylene glycols), propylene glycol,Tween 80 (polyoxyethylene (20) sorbitan monooleate) or a mixture of twoor more of these materials. Accordingly the product is preferablypackaged for storage and use either in the anhydrous state or formulatedin compositions using the above or similar nonaqueous carrier materials.

As a further characterization of the compound of this invention, it wasacetylated by standard procedures with acetic anhydride to produceocta-acetyl-1,4-bis(D-glucosyl)piperazine; M.P. 236-237 C. (d).

While several particular embodiments of this invention are shown above,it will be understood of course that the invention is not to be limitedthereto since modifications may be made and it is contemplated thereforeby the'appended claims to cover any such modifications as fall withinthe true spirit and scope of this invention.

I claim:

1 1,4-bis (D-glucosyl) piperazine.

2. A process of preparing 1,4-bis(D-glucosyl)pipera zine which comprisescontacting glucose and piperazine for a period of time until a solidproduct is formed and separating said product from the reaction mixture.

No references cited.

1. 1,4-BIS(D-GLUCOSYL) PIPERAZINE.
 2. A PROCESS OF PREPARIONG1.4-BIS(D-GLUCOSY) PIPERAZINE WHICH COMPRISES CONTACTING GLUCOSE ANDPIPERAZINE FOR A PERIOD OF TIME UNTIL A SOLID PRODUCT IS FORMED ANDSEPARATING SAID PRODUCT FROM THE REACTION MIXTURE.